[Objective] The degree of uncoordinated coupling between high-quality development and ecological protection was measured scientifically in order to promote the high-quality development and ecological protection of the Yangtze River Economic Belt. [Methods] A comprehensive evaluation index system was constructed for high-quality development and ecological protection for 108 cities in the Yangtze River Economic Belt. We used uncoordinated coupling, spatial autocorrelation, and other methods to explore the uncoordinated coupling relationship between high-quality development and ecological protection in the Yangtze River Economic Belt from 2005 to 2018. [Results] ① As time progressed, the gap in ecological protection between cities decreased, but the gap in high-quality development increased, and the degree of uncoordinated coupling between the two systems showed a fluctuating downward trend. ② Cities with a degree of uncoordinated coupling less than or equal to 0.5 were mainly concentrated in the downstream region and gradually spread to the middle and upper reaches of the Yangtze River. ③ The degree of uncoordinated coupling between high-quality development and ecological protection in the Yangtze River Economic Belt showed positive spatial autocorrelation, and the spatial agglomeration effect was significant. [Conclusion] There was a large difference in the degree of uncoordinated coupling between the high-quality development and ecological protection of cities. The key to breaking uncoordinated coupling based on ecological protection is to give full attention to the leading role of urban agglomerations and provincial capital cities.